Cytotoxic T Lymphocyte Response to Influenza Virus

University Of Virginia, Charlottesville VA

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Abstract

DESCRIPTION (provided by applicant): Type A influenza virus (IAV) is a major human pathogen with the capacity to rapidly spread world-wide and to produce severe and sometimes fatal infections resulting in severe pneumonia. Evidence accumulating over the past several decades strongly suggests that disease produced by IAV infection not only reflects the extent of virus replication in the respiratory tract, but also the strength or magnitude of the host innate ad adaptive immune response. Our laboratory has had longstanding interest (over 30 yrs duration) in understanding the role of the adaptive immune CD8+ CTL (CD8+ Te) response in IAV clearance from the infected lungs and in the development of associated pulmonary inflammation and injury. This renewal application builds on recent findings from our laboratory suggesting that pro-inflammatory mediator production by CTL is triggered by recognition of IAV antigen bearing CD45+ inflammatory cells infiltrating the IAV infected pulmonary interstitium while CTL encounter with and recognition of CD45- IAV infected respiratory epithelial cells results in the elimination of these productively-infected cells without triggering inflammatory mediator production of the CTL. The studies described here, which utilize a murine model and primary human cells, are designed to identify the CD45+ inflammatory cell types within the IAV infected respiratory tract that trigger CTL, and the role of costimulatory ligands displayed by these cells in triggering mediator production by CTL. Companion studies will examine the interaction of CTL with CD45- IAV infected respiratory epithelial cells using differentiated primary epithelial cells. We will use this information to explore strategies to selectively suppress excess pulmonary inflammation associated with CTL recognition of CD45+ inflammatory cells in the IAV infected lungs without altering virus clearance from lungs. The Specific Aims of this program are: 1) To evaluate the contribution of specific CD45+ Inflammatory Cell subsets in the induction of pro-inflammatory mediator production by IAV-specific CTL in the infected RT; 2) To determine the properties of murine and human respiratory epithelial cells (REC) which renders these cells capable of triggering CD8+ Te-mediated cytolysis, but not pro-inflammatory cytokine production; 3) To assess the impact of modulation of co-stimulatory ligands on CTL effector activity in vivo, virus elimination and pulmonary inflammation. The proposed studies should provide a framework for the development of new therapeutic strategies to control the severity of IAV infection.